Process for the production of 2, 2-dialkyl androstane compounds



Patented Mar. a1, leer PROCESS FOR THE PRODUCTION OF 2,2-DIALKYLANDROSTANE COMPOUNDS 5 Howard J. Ringold and George Rosenkranz, MexicoCity, R

Mexico, assignors to Syntex S.A., Mexico City, Mexico, a corporation ofMexico No Drawing. Filed Mar. 11, 1957, Ser. No. 644,970

Claims priority, application Mexico Mar. 14, 1956 3 Claims. (Cl.260397.4)

and

In the above formulas R represents an alkyl group preferably a loweralkyl group of less than 7 carbon atoms such as methyl, ethyl or propyl.R represents hy drogen or an acyl group of the type conventionally foundin an esterified steroid alcohols. These are generally those derivedfrom a hydrocarbon carboxylic acid of less than 12 carbon atoms such asacetic, propionic, butyric, valeric, hexanoic, caprylic, hydrocinnamiccyc1o-, pentylpropionic, benzoic etc. R represents a lower alkyl groupof less than 7 carbon atoms such as methyl, ethyl or propyl. Xrepresents a double bond between -4 and C or a saturated linkage between0-4 and C-5.

The novel compounds of the present invention may be prepared by aprocess illustrated in part bythe following equations: 1

The present invention relates to novel cyclopentanophenanthrenederivatives and to a process for the production thereof.

More particularly the present invention relates to novel androgenichormones which are 2,2-dia1kyl derivatives of testosterone,dihydrotestosterone, 17-lower alkyl testosterone and 17-lower alkyldihydrotestosterone. The present invention also relates to activehormones of the androgen type which are the corresponding 3-hydroxyderivatives of the aforementioned compounds. The novel useful androgensof the present invention differ substantially from the correspondingcompounds without a 2,2- dialkyl substituent especially in that theyhave a different or higher androgenic-anabolic ratio.

It has been discovered in accordance with the present invention thattreatment of dihydrotestosterone (androstan-17fl-ol-3-one) or 17-loweralkyl-dihydrotestosterone (l7a-lower alkyl-androstan-17B-ol-3-one) witha lower alkyl iodide in the presence of a potassium t-alkoxide R iodideresulted in the production of the corresponding novel 2,2-di lower alkylderivatives i.e. 2,2-di lower alkyl-am drostan-17fi-ol-3-one and2,2,17a-tri-lower alkyl-androstan-l7B-ol-3-one. Further in accordancewith the present invention it has been discovered that monobromination,of the aforementioned compounds gave the corremqnobrommatlon sponding4-bromo-2,2-di lower alkyl or 2,2,17oc-t1'i lower v|alkylandrostan-17B-ol-3-one compounds which on dehydrobromination gavethe corresponding novel 2,2-di

lower alkyl or 2,2,17a-tri lower alkyl A -androsten-17fl- R ol-3-onecompounds. All of these novel compounds R dehydrobro- R I minetion upontreatment with a reducing agent gave the come sponding novel 3-hydroxyderivatives. By conventional esterification there was also prepared theesters of those compounds wherein the alcohol groups were non-tertiary.The novel compounds of the present invention may therefore be indicatedby the following formulas:

RANV

R M t-alkoxide, such as potassium t-butoxide, and the mixture;

' stirred under nitrogenatmosphere for a shorttime. such M as half anhour. An excess of a lower alkyl iodide such as methyl, ethyl or propyliodide is then added and reaction mixture stirred for ,a longer periodof t of the order of 4 hours. Water is then added, the solution isneutralized with acid and the organic solvent is removed by reducedpressure distillation. The residue is then collected by filtration andpurified to give the respective 2,2-di lower alkyl or 2,2,17a-tri loweralkylandrostan-17B-ol-3-one. By conventional esterification proceduressuch as reaction with acetic anhydride or other acid anhydrides orchlorides of the type previously described there is then prepared thecorresponding 17- acylates of hydrocarbon carboxylic acids of less than12 carbon atoms of the 2,2-di lower alkyl compounds.

To prepare the corresponding A compounds the 2,2- di lower alkyl or the2,2,l7a-tri lower alkyl derivatives or the 17-esters of the 2,2-di loweralkyl derivatives are treated with slightly over 1 molar equivalent ofbromine to prepare the corresponding 4-monobromo compounds.Dehydrobromination of the 4-bromo compounds as with a tertiary aminesuch as collidine gave the corresponding M-compounds i.e. 2,2-di loweralkyl-M-androsten-175-01- 3-one and its 17-esters or 2,2,17a-tri loweralkyl M-androsten-17B-ol-3-one.

As illustrated in the second equation treatment of the compounds justmentioned, the previously set forth 2,2-di lower alkyl or 2,2,l7a-trilower alkyl-saturated compounds with a reducing agent such as sodiumborohydride gives 3-hydroxy derivatives. Thus from 2,2-di loweralkyl-androstan-l7 3-ol-3-one there is prepared the corresponding 2,2-dilower alkyl-3,17;9-diol derivatives,

from 2,2,l7oc-tri lower alkyl-androstan-17fi-ol-3-one, the

corresponding 2,2-17a-tri lower alkyl-androstan-3,17fldiol derivatives,from 2,2-di lower alkyl-A androsten- 17B'ol, the corresponding 2,2-dilower alkyl-A androsten-3,17p-dio1 and from 2,2,17a-tri lower alkyl-A-androsten-l7f3-ol-3-one, the corresponding 2,2,17a-tri lower alkyl-A-androsten-3,17fl-diol derivatives. By conventional esterificationprocedures the previously described esters of these compounds wereprepared i.e. the 3,17-diesters of 2,2-di lower alkyl derivatives andthe 3-monoesters of the 2,2,l7u-tri lower alkyl derivatives.

The following specific examples serve to illustrate but are not intendedto limit the present invention.

Example I A suspension of 5 g. of dihydrotestosterone in 40 cc. oft-butanol was mixed with 3 molar equivalents of potassium t-butoxide in60 cc. of t-butanol and the mixture was stirred under an atmosphere ofnitrogen for 30 minutes. 6 molar equivalents of methyl iodide was addedand stirred for 4 additional hours. Water was added, the solution wasneutralized with acetic acid and the organic solvent was removed bydistillation under reduced pressure. The residue was collected byfiltration, dried and chromatographed in a column of ethyl acetatewashed alumina, thus yielding 2.5 g. of2,2-dimethyl-androstan-17,3-01-3-one having a melting point of 134136 C.[a] +72".

Upon conventional esterification with acetic anhydride there wasprepared the l7-acetate of 2,2-dimethyl-androstan-17fl-ol-3-one with amelting point of 138-140 C. In a similar conventional way there was alsoprepared the propionate, butyrate, cyclopentylpropionate and benzoate.

Example 11 5 g. of 17-methyl-dihydrotestosterone was treated such asdescribed in Example I to produce2,2,17-trimethylandrostan-l7fl-ol-3-one having a melting point of 117-120 C., [oc] +53.

Similarly, there were obtained the corresponding17apropyldihydrotestosterone respectively.

Example III A solution of 1.1 molar equivalents of bromine in 5 cc. ofchloroform was added dropwise and under continuous stirring to asolution of 1 g. of 2,2-dimethyl-androstan-17p-ol-3-one in 20 cc. ofchloroform, and once the solution had decolorized it was washed withwater, with dilute sodium bicarbonate solution and water, dried oversodium sulfate and evaporated to dryness under reduced pressure, thusproducing 4-bromo-2,2-dimethyl-androstan-17/3-ol-3-one.

This product was heated under reflux for l hour with 10 cc. ofcollidine. The cooled mixture was diluted with ethyl acetate, andfiltered and the ethyl acetate solution was washed with dilute sulfuricacid and water, dried and evaporated to dryness. Chromatography of theresidue afforded 500 mg. of 2,2-dimethyl-testosterone.

The 17-acetate of 2,2-dimethyl-androstan-17/3-ol-3-one upon treatmentwith 1.1 molar equivalents of bromine gave the l7-acetate of4-bromo-2,2-dimethyl-androstan- 17B-ol-3-one having a melting point of146-148 C., [11] +13. Dehydrobromination of this compound with collidinegave the l7-acetate of 2,2-dimethyl-testosterone with a melting point ofI'll-173 C., [a] +44. Similar treatment of the other esters described inExample I gave the corresponding esters of 2,2-dimethyl-testosterone.

1 g. of 2,2-dimethyl-testosterone, dissolved in 30 cc. of methanol, Wastreated with 200 mg. of sodium borohydride and the mixture was refiuxedfor 1 hour, cooled and treated dropwise with acetic acid to destroy theexcess of hydride. The mixture was poured into water, extracted withmethylene dichloride and evaporated to dryness leaving as a residue2,2-dimethyl-A -androsten- 3,17/3-diol.

Conventional esterification with acetic anhydride gave the3,17-diacetate of 2,2-dimethyl-A -androsten-3,17fldiol and in a similarway there was also prepared the dipropionate, dibutyrate and dibenzoate.

Example IV 1 g. of the 2,2-dimethyl-dihydrotestosterone, obtained inaccordance with Example I, was treated by the procedure described in thelast paragraph of Example 111, thus giving 2,2dimethyl-androstan3,l7B-diol.

By following the procedure of Example III from2,2,17a-trimethyl-androstan-17,8-01-3-one there was obtained2,2,17a-trimethyl-A -androsten-17fi-ol-3-one and from this compoundthere was obtained 2,2,l7e-trimethyl-M-androstan-B,17,3-diol. Similarlyfrom 2,2-dimethyl-17u-ethyl-androstan-17B-ol-3-one there was obtained2,2 dimethyl 17a ethyl-Mandrosten-l7,8-ol-3-one and from this lastcompound 2,2-dimethyl-l7a-ethyl-A -androsten-3-l7fl-diol. The2,2-dimethyl-17x-propyl-A -androsten-l7fi-ol-3-one and the2,2-dimethyl-l7a-propyl-A -androsten-3,l7,B-diol derivatives were alsoprepared from 2,2-dimethyl-l7a-propyl-androstan-l7fl-ol-3-one. Byconventional esterification procedures there was prepared 3-monoestersof these trialkyl compounds as the 3 -acetate, 3-propionate,3-cyclopentylpropionate and 3-benzoate.

We claim:

1. A process for the production of compounds selected from the groupconsisting of 2,2-lower alkyl-A -androsten-17fi-ol-3-one and 2,2,17e-trilower allcyl-M-ITB-ol- 3-one comprising reacting respectively a compoundselected from the group consisting of androstan-l7fi-ol-3- one and17a-lower alkyl-androstan-17 3-ol-3-one with an excess of a lower alkyliodide in the presence of a potassium t-alkoxide to form a corresponding2,2-di lower alkyl derivative, reacting the 2,2-di lower alkylderivative with approximately 1 molar equivalent of bromine to form acorresponding 4-monobromo compound and refluxing the 4-monobromocompound with collidine.

2. The process of claim 1 wherein the allzyl iodide is methyl iodide andthe final compound is a 2,2-dimethyl derivative.

3. The process of claim 1 wherein alkyl iodide is methyl iodide, thepotassium t-alkoxide is potassium t-butoxide, the dehydrobrominatingagent is collidine and the final product is a 2,2-dimethyl derivative.

(References on following page) Fieser et al.: Natural Products Relatedto Phenanthrene, 1949, pages 375-376.

Therapie, Digonnet et al., v01. 9 (1954), pages 36- 42 relied on orChem. Abstracts, Vol. 48, pars. 13975 (b).

Woods et aL: Jour. Chem. Society (1955), pages 3426-30 relied on.

Julia: Ann. Chem. (Paris), V0158, pages 410-49 rei lied on (1953).

Rome: B01. Inst. Quim. Univ. Nacl. Autong Mexicp, .J- i 7' vol. 4(1952), pages 91-100 relied on. I 3

1. A PROCESS FOR THE PRODUCTION OF COMPOUNDS SELECTED FROM THE GROUPCONSISTING OF 2,2-LOWER ALKYL-$4-ANDROSTEN-17B-OL-3 ONE AND 2,2,17A-TRILOWER ALKYL-$4-17B-OL3-ONE COMPRISING REACTING RESPECTIVELY A COMPOUNDSESELECTED FROM THE GROUP CONSISTING OF ANDROSTAN-17B-OL-3ONE AND17A-LOWER ALKALY-ANDROSTAN-17B-OL-3-ONE WITH AN EXCESS OF A LOWER ALKYLIODIDE IN THE PRESENCE OF A POTASSIUM T-ALKOXIDE TO FORM A CORRESPONDING2,2-DI ALKYL DERIVATIVE, REACTING THE 2,2-DI LOWER ALKYL DERIVATIVE WITHAPPROXIMATELY 1 MOLAR EQUIVALENT OF BROMINE TO FORM A CORRESPONDING4-MONOBROMO COMPOUND AND REFLUXING THE 4-MONOBROMO COMPOUND WITHCOLLIDINE.